Pharmaceutical compositions and methods of use 4-pregenen-11β-17-21-triol-3,20-dione derivatives

ABSTRACT

The present invention relates to pharmaceutical compositions comprising 4-pregenen-11β-17-21-triol-3,20-dione derivatives, and their use as pharmaceuticals as modulators of the glucocorticoid receptors (GR) and/or the mineralocorticoid receptors (MR). The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat ocular conditions associated with the glucocorticoid receptors (GR) and/or the mineralocorticoid receptors (MR).

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/558,775, filed Nov. 11, 2011, the disclosure of which is herebyincorporated in its entirety herein by reference

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising4-pregenen-11β-17-21-triol-3,20-dione derivatives, and their use aspharmaceuticals as modulators of the glucocorticoid receptors (GR)and/or the mineralocorticoid receptors (MR). The invention relatesspecifically to the use of these compounds and their pharmaceuticalcompositions to treat ocular conditions associated with theglucocorticoid receptors (GR) and/or the mineralocorticoid receptors(MR).

BACKGROUND OF THE INVENTION

Glucocorticoid (GC) agonists represent a class of anti-inflammatorycompounds that are useful in treating multiple ocular conditionsincluding elevated intraocular pressure, glaucoma, uveitis, retinal veinocclusions, macular degeneration, diabetic retinopathy, various forms ofmacular edema, post-surgical inflammation, inflammatory conditions ofthe palpebral and bulbar conjunctiva, cornea, and anterior segment ofthe globe, such as allergic conjunctivitis, ocular rosacea, dry eye,blepharitis, retinal detachment, meibomian gland dysfunction (MGD),superficial punctate keratitis, herpes zoster keratitis, iritis,cyclitis, selected infective conjunctivitis, corneal injury fromchemical, radiation, or thermal burns, penetration of foreign bodies,allergy, or combinations thereof.

A potential use limiting and sight-threatening side-effect oftraditional GC agonist therapies (e.g. fluocinolone acetonide) is ocularhypertension that is likely generated by an increased resistance ofaqueous humor flow through the trabecular meshwork. The mechanism of GCagonist-induced outflow resistance and subsequent ocular hypertension isnot well understood.

As such, GC modulation through agonist or antagonist activity of GCreceptors that does not result in increased intraocular pressure orother side effects is needed in the art and is described herein.

SUMMARY OF THE INVENTION

It has now been discovered the use of a group of4-pregenen-11β-17-21-triol-3,20-dione derivatives as potent andselective glucocorticoid receptors (GR) and/or the mineralocorticoidreceptors (MR). As such, the compounds described herein are useful intreating a wide variety of disorders associated with modulation of theglucocorticoid receptors (GR) receptor or the mineralocorticoidreceptors (MR). The term “modulator” as used herein, includes but is notlimited to: receptor agonist, antagonist, inverse agonist, inverseantagonist, partial agonist, partial antagonist.

The present invention relates to pharmaceutical compositions comprising4-pregenen-11β-17-21-triol-3,20-dione derivatives useful in treating oneor more ocular conditions. Methods of treating one or more ocularconditions are also disclosed. Ocular conditions treated using compoundsand/or formulations described herein include, but are not limited to,elevated intraocular pressure, glaucoma, uveitis, retinal veinocclusions, macular degeneration, diabetic retinopathy, various forms ofmacular edema, post-surgical inflammation, inflammatory conditions ofthe palpebral and bulbar conjunctiva, cornea, and anterior segment ofthe globe, such as allergic conjunctivitis, ocular rosacea, dry eye,blepharitis, retinal detachment, meibomian gland dysfunction (MGD),superficial punctate keratitis, herpes zoster keratitis, iritis,cyclitis, selected infective conjunctivitis, corneal injury fromchemical, radiation, or thermal burns, penetration of foreign bodies,allergy, or combinations thereof.

The present invention relates to a method of treating a disorderassociated with modulation of the glucocorticoid receptors (GR) and/orthe mineralocorticoid receptors (MR), which comprises administering atherapeutically effective amount of a composition comprising a4-pregenen-11β-17-21-triol-3,20-dione derivative. The compounds inaccordance with the present invention are thus of use in medicine, forexample in the treatment of humans with diseases and conditions that arealleviated by glucocorticoid or mineralocorticoid receptors modulation.

In one aspect, the invention provides a pharmaceutical composition of a4-pregenen-11β-17-21-triol-3,20-dione derivative selected from the groupof compounds from Table 1:

TABLE 1 Compound IUPAC name Structure 1 (8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13- dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl phenylacetate

2 (8S,9S,10R,11S,13S,14S,17R)- 17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl butyrate

3 (8S,9S,10R,11S,13S,14S,17R)- 17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl propionate

4 (8S,9S,10R,11S,13S,14S,17R)- 17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl octanoate

5 (8S,9S,10R,11S,13S,14S,17R)- 17-Glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl hexanoate

6 (8R,9R,10S,11R,13R,14R,17S)- 17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl benzoate

7 (8S,9S,10R,11S,13S,14S,17R)- 17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl heptanoate

8 (8S,9S,10R,11S,13S,14S,17R)- 17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl 2- methylpropanoate

9 (8R,9R,10S,11R,13R,14R,17S)- 17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl rel-cyclopentanecarboxylate

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Table 1 are able to form.

The acid addition salt form of a compound of the invention that occursin its free form as a base can be obtained by treating the free basewith an appropriate acid such as an inorganic acid, such as for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid and the like; or an organic acid such as for example,acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaricacid, maleic acid, oxalic acid, tartaric acid, succinic acid, malicacid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric,methylsulfonic, ethanesulfonic, benzenesulfonic, formic and the like(Handbook of Pharmaceutical Salts, P. Heinrich Stahal& Camille G.Wermuth (Eds), Verlag Helvetica Chemica Acta—Zürich, 2002, 329-345).

The base addition salt form of a compound of the invention that occursin its acid form can be obtained by treating the acid with anappropriate base such as an inorganic base, for example, sodiumhydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide,ammonia and the like; or an organic base such as for example,L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like.(Handbook of Pharmaceutical Salts, P. Heinrich Stahal& Camille G.Wermuth (Eds), Verlag Helvetica Chemica Acta—Zürich, 2002, 329-345).

Compounds of the invention and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

The compounds described herein are useful in treating a variety ofocular conditions including, but not limited to elevated intraocularpressure, glaucoma, uveitis, retinal vein occlusions, maculardegeneration, diabetic retinopathy, various forms of macular edema,post-surgical inflammation, inflammatory conditions of the palpebral andbulbar conjunctiva, cornea, and anterior segment of the globe, such asallergic conjunctivitis, ocular rosacea, dry eye, blepharitis, retinaldetachment, meibomian gland dysfunction (MGD), superficial punctatekeratitis, herpes zoster keratitis, iritis, cyclitis, selected infectiveconjunctivitis, corneal injury from chemical, radiation, or thermalburns, penetration of foreign bodies, allergy, or combinations thereof.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation of the glucocorticoidreceptors (GR) and/or the mineralocorticoid receptors (MR). Such methodscan be performed, for example, by administering to a subject in needthereof a therapeutically effective amount of at least one compound ofTable 1, or any combination thereof, or pharmaceutically acceptablesalts thereof.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of Table 1 in a pharmaceuticallyacceptable carrier.

The compounds described herein may be administered at pharmaceuticallyeffective dosages. Such dosages are normally the minimum dose necessaryto achieve the desired therapeutic effect. Generally, such doses will bein the range of about 1 mg/day to about 1000 mg/day; more preferably inthe range of about 10 mg/day to about 500 mg/day. In another exampleembodiment, the compound or compounds may be present in a composition orformulation in a range of about 0.5 mg/kg/day to about 100 mg/kg/day orabout 1 mg/kg/day to about 100 mg/kg/day. However, the actual amount ofthe compound to be administered in any given case will be determined bya physician taking into account the relevant circumstances, such as theage and weight of the patient, the patient's general physical condition,the severity of ocular condition, and the route of administration. Insome instances, dosing is evaluated on a case-by-case basis.

In another example embodiment, provided are pharmaceutical compositionsincluding at least one compound in a pharmaceutically acceptablecarrier. Pharmaceutical compositions can be used in the form of a solid,a solution, an emulsion, a dispersion, a micelle, a liposome, and thelike, wherein the resulting composition contains one or more compoundsdescribed herein, as an active ingredient, in admixture with an organicor inorganic carrier or excipient suitable for enteral or parenteralapplications. One or more compounds may be combined, for example, withthe usual non-toxic, pharmaceutically acceptable carriers for tablets,pellets, capsules, suppositories, solutions, emulsions, suspensions, andany other form suitable for use. The carriers which can be used includeglucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Compoundsdescribed herein are included in pharmaceutical compositions in anamount sufficient to produce the desired effect upon the process ordisease condition.

In another embodiment, the compounds described herein can beadministered orally in any acceptable form, such as a tablet, liquid,capsule, powder and the like. However, other routes may be desirable ornecessary, particularly if the patient suffers from nausea. Such otherroutes may include, without exception, transdermal, parenteral,subcutaneous, intranasal, intrathecal, intramuscular, intravenous, andintrarectal modes of delivery. Additionally, formulations may bedesigned to delay release of the active compound over a given period oftime, or to carefully control the amount of drug released at a giventime during the course of therapy.

Pharmaceutical compositions in a form suitable for oral use, forexample, are administered as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of a sweetening agent such assucrose, lactose, or saccharin, flavoring agents such as peppermint, oilof wintergreen or cherry, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations. Tabletscontaining compounds described herein in admixture with non-toxicpharmaceutically acceptable excipients may also be manufactured by knownmethods.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

Described herein are compounds capable of modulating glucocorticoidreceptors (GR) and/or mineralocorticoid receptors (MR). The compoundsdescribed can have greater GR activation and/or binding potency comparedto a compound such as cortisol. As such, the compounds can efficientlytreat ocular indications. The compounds can further be metabolized byesterase enzymes within the eye to form the natural agonist cortisol,thereby reducing the risk of ocular hypertension. The cortisol remainingwithin the eye and body is further metabolized to inactive compounds vianaturally occurring dehydroxylases and other enzymes making this a safetherapeutic approach.

In patients, the naturally occurring endogenous GC agonist cortisol(hydrocortisone) has a minimal effect on intraocular pressure whenapplied locally via eye drops compared to synthetic GCs such asdexamethasone, prednisolone, and fluorometholone (Cantrill et al.,1975). Further support of the overall superior safety of cortisol as atherapeutic is the fact that various topical hydrocortisone formulationsare currently sold over the counter directly to consumers.

Without wishing the bound to any particular theory, it was surprisinglydiscovered that the presently described compounds can have moreglucocorticoid receptor modulation than cortisol because of themodification to the 17-position of the cortisol molecule.

As used herein, the term “therapeutically effective amount” means theamount of the pharmaceutical composition that will elicit the biologicalor medical response of a subject in need thereof that is being sought bythe researcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The excipients used may be, for example, (1) inert diluents such ascalcium carbonate, lactose, calcium phosphate or sodium phosphate; (2)granulating and disintegrating agents such as corn starch, potato starchor alginic acid; (3) binding agents such as gum tragacanth, corn starch,gelatin or acacia, and (4) lubricating agents such as magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the compounds are mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin.They may also be in the form of soft gelatin capsules wherein thecompounds are mixed with water or an oil medium, for example, peanutoil, liquid paraffin, or olive oil.

The compounds described herein can also be administered as anophthalmically acceptable formulation or composition. A liquid which isophthalmically acceptable is formulated such that it can be administeredtopically to the eye. The comfort should be maximized as much aspossible, although sometimes formulation considerations (e.g. stability)may necessitate less than optimal comfort. In the case that comfortcannot be maximized, the liquid should be formulated such that theliquid is tolerable to the patient for topical ophthalmic use.Additionally, an ophthalmically acceptable liquid should either bepackaged for single use, or contain a preservative to preventcontamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in ophthalmic compositions describedherein include, but are not limited to, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuricnitrate. A useful surfactant is, for example, Tween 80. Likewise,various useful vehicles may be used in the ophthalmic preparationsdescribed herein. These vehicles include, but are not limited to,polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor. Various buffers and means for adjusting pHmay be used so long as the resulting preparation is ophthalmicallyacceptable. Accordingly, buffers include acetate buffers, citratebuffers, phosphate buffers and borate buffers. Acids or bases may beused to adjust the pH of these formulations as needed.

In one example embodiment, an ophthalmic composition as described hereinmay have ingredients used in the following amounts listed in Table 2.

TABLE 2 Ingredient Amount (% w/v) active ingredient about 0.001-5preservative  0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer0.01-10   pH adjustor q.s. pH 4.5-7.5 antioxidant as needed surfactantas needed purified water as needed to make 100%

In other embodiments, the ophthalmically acceptable liquid can beformulated for intraocular injection. The compounds described herein canbe formulated as a liquid, gel, paste, cream, oil. Further, thecompounds can be formulated into sustained release or controlled releaseintraocular implants comprising biodegradable polymers such aspolylactic acid, poly glycolic acid, combinations thereof and the like.

Some exemplary compositions can include a combination of two or morecompounds as described herein. Different ratios of compounds can beformulated depending on a particular ocular condition or set ofconditions being treated.

Since individual subjects may present a wide variation in severity ofsymptoms and each composition has its unique therapeuticcharacteristics, the precise mode of administration and dosage employedfor each subject is left to the discretion of the practitioner.

DETAILED DESCRIPTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Example 1 Glucocorticoid Receptor Transactivation Potencies for Cortisoland 17-ester Derivatives

Glucocorticoid receptor (GR) activation potency was assessed using aHeLa cell line containing the MMTV-bla reporter (MMTV-bla HeLaCELLSENSOR®, Invitrogen Corp., Carlsbad, Calif.). This cell line wasstably transfected with an expression construct containing β-lactamasecDNA under control of the MMTV response element previously identified asa glucocorticoid receptor response element.

Results from one experiment performed in duplicate for 9 compounds andthe control compound, dexamethasone, are summarized in Table 3. Allassays were performed as 10-point dose responses using a half log-folddilution series starting with a maximum compound concentration of 100nM. The compounds were incubated for 5 hours. The activation ofendogenous GR leads to expression of the reporter μ-lactamase which isdetected by the conversion of a FRET substrate in a ratiometric assayformat. This functional assay allows for measurement of receptor agonismby compounds and can be used to determine compound potency andselectivity. Assay reproducibility was determined by calculating Z′values for untreated versus maximum stimulation. The Z′ value wasgreater than 0.6, indicating good reproducibility of the assay format.

Several compounds showed dose-dependent stimulation of the GR signalingpathway (Table 3). Compounds of Table 1 showed about 30-fold greaterpotency compared to the parent molecule cortisol.

TABLE 3 Glucocorticoid receptor potency. Shown are the EC₅₀ (nM) and Z′values for the control compound, dexamethasone, and compounds tested inagonist mode. EC50 % Activation Compound (nM) GR at 100 nM Z′

1.05 Control Compound 0.87

1.35 88 0.87

1.41 85 0.87

1.97 86 0.87

3.25 65 0.87

6.04 47 0.87

6.31 85 0.87

7.07 84 0.87

41.6 43 0.87

>100 15 0.87

>100 5 0.87

Example 2 Mineralocorticoid Receptor Transactivation Potencies forCortisol and 17-ester Derivatives

Mineralocorticoid receptor (MR) activation potency was assessed using aHEK 293T cell line containing the UAS-bla reporter (UAS-bla HEK 293TCELLSENSOR®). This cell line was stably cotransfected with an expressionconstruct containing β-lactamase cDNA under control of the GAL4 UpstreamActivator Sequence (UAS) and another expression construct encoding forthe fusion protein GAL4(DBD)-MR(LBD). Results for one experimentperformed in duplicate for 9 compounds and the control compound,aldosterone, in agonist mode are summarized in Table 4. All assays wereperformed as 10-point dose responses using a half log-fold dilutionseries starting with a maximum compound concentration of 100 nM. Thecompounds were incubated for 16 hours. The activation of the fusionprotein GAL4(DBD)-MR(LBD) leads to expression of the reporterβ-lactamase which is detected by the conversion of a FRET substrate in aratiometric assay format. This functional assay allows for measurementof receptor agonism by compounds and can be used to determine compoundpotency and selectivity. Assay reproducibility was determined bycalculating Z′ values for untreated versus maximum stimulation. The Z′value was greater than 0.6, indicating good reproducibility of the assayformat. Several compounds showed dose-dependent stimulation of the MRsignaling pathway (Table 4).

TABLE 4 Mineralocorticoid receptor potency. Shown are the EC₅₀ (nM) andZ′ values for the control compound, aldosterone, and all 10 compoundstested in agonist mode. EC50 % Activation Compound (nM) GR at 100 nM Z′

0.47 Control Compound 0.77

2.85 81 0.77

2.90 75 0.77

2.94 77 0.77

3.17 76 0.77

5.27 72 0.77

5.68 64 0.77

7.46 62 0.77

9.29 56 0.77

15.6 62 0.77

>100 27 0.77

Example 3 Treating Elevated Intraocular Pressure

A 58 year old male visits his ophthalmologist for a routine check-up.The physician discovers that the patient exhibits an elevatedintraocular pressure and is at high risk for future complications. Thepatient is instructed to apply a topical liquid formulation containingone of the compounds in Table 1 once daily to each eye.

The patient returns for a follow-up visit three months later. Uponmeasuring intraocular pressure, it is noted that the patient nowexhibits a reduced intraocular pressure.

Example 4 Treating Ocular Irritation

A 38 year old male visits his ophthalmologist complaining of irritationin his right eye. The physician discovers that the patient's right eyeis inflamed and red. The patient is instructed to apply a topical liquidformulation containing one of the compounds in Table 1 twice daily tothe right eye.

The patient returns for a follow-up visit a week later. Upon inspectionof the right eye, it is noted that the patient's eye is no longer redand the patient indicates that the irritation is gone.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.”

Accordingly, unless indicated to the contrary, the numerical parametersset forth in the specification and attached claims are approximationsthat may vary depending upon the desired properties sought to beobtained by the present invention. At the very least, and not as anattempt to limit the application of the doctrine of equivalents to thescope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

What is claimed is:
 1. A method of treating an ocular conditionassociated with glucocorticoid and/or mineralocorticoid receptormodulation which comprises topically administering to a patient in needthereof, a pharmaceutical composition comprising a therapeuticallyeffective amount of at least one compound selected from: the groupconsisting of(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylphenylacetate;(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylbutyrate;(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylpropionate;(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yloctanoate;(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylhexanoate;(8R,9R,10S,11R,13R,14R,17S)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylbenzoate;(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylheptanoate;(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl2-methylpropanoate; and(8R,9R,10S,11R,13R,14R,17S)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylrel-cyclopentanecarboxylate.
 2. The method according to claim 1 whereinthe ocular condition is selected from elevated intraocular pressure,glaucoma, uveitis, retinal vein occlusions, macular degeneration,diabetic retinopathy, various forms of macular edema, post-surgicalinflammation, inflammatory conditions of the palpebral and bulbarconjunctiva, cornea, and anterior segment of the globe, such as allergicconjunctivitis, ocular rosacea, dry eye, blepharitis, retinaldetachment, meibomian gland dysfunction, superficial punctate keratitis,herpes zoster keratitis, iritis, cyclitis, selected infectiveconjunctivitis, corneal injury from chemical, radiation, or thermalburns, penetration of foreign bodies, allergy, and combinations thereof.3. The method according to claim 1 wherein the ocular condition isselected from, ocular rosacea, dry eye, blepharitis, meibomian and glanddysfunction.
 4. The method according to claim 1 wherein the compound is:(8R,9R,10S,11R,13R,14R,17S)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylbenzoate.
 5. The method according to claim 1 wherein the compound is:(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylhexanoate.
 6. The method according to claim 1 wherein the compound is:(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yloctanoate.
 7. The method according to claim 1 wherein the compound is:(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylphenylacetate.
 8. The method according to claim 1 wherein the compoundis:(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylbutyrate.
 9. The method according to claim 1 wherein the compound is:(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylpropionate.
 10. The method according to claim 1 wherein the compound is:(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylheptanoate.
 11. The method according to claim 1 wherein the compound is(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl2-methylpropanoate.
 12. The method according to claim 1 wherein thecompound is(8R,9R,10S,11R,13R,14R,17S)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylrel-cyclopentanecarboxylate.